Compounded compositions and methods for treating pain

ABSTRACT

A compounded capsule may include cannabidiol powder for combining with a solution, cream, gel, suspension or ointment for administration to a skin surface. The compounded capsule may also include xylitol powder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 16/867,057, filed May 5, 2020, now U.S. Pat. No. 10,966,946,which is a continuation-in-part of U.S. patent application Ser. No.16/735,174, filed Jan. 6, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/381,967, filed Apr. 11, 2019, now U.S. Pat. No.10,525,025, which is a continuation-in-part of U.S. patent applicationSer. No. 16/010,731, filed Jun. 18, 2018, which is a divisional of U.S.patent application Ser. No. 15/354,630 filed Nov. 17, 2016, now U.S.Pat. No. 9,999,604. The disclosures of U.S. patent application Ser. No.16/735,174, U.S. patent application Ser. No. 16/381,967, U.S. patentapplication Ser. No. 16/010,731, and U.S. patent application Ser. No.15/354,630 are hereby incorporated by reference herein.

TECHNICAL FIELD

The present application relates to compounded medications. Inparticular, the present application relates to topical compositionscomprising cannabidiol, lidocaine, prilocaine, diclofenac, xylitol,and/or poloxamers and methods of making and using such topicalcompositions.

BACKGROUND

Pain is often treated with medication such as anti-inflammatory or localanesthetic drugs. Treatment can include administration of the medicationvia oral, intramuscular, subcutaneous, intravenous, and topical routes.

Cannabidiol (CBD) is a non-psychoactive cannabinoid agent found incannabis species such as the hemp plant (Cannabis sativa L.) as well asother sources. It is an active ingredient in the FDA approved drugproduct EPIDIOLEX®, which is used to treat seizures. The FDA considerscannabidiol powder an API/drug, but it is not a controlled substanceaccording to the DEA.

Diclofenac sodium topical solution is a non-steroidal anti-inflammatorydrug (NSAID) indicated for the treatment of signs and symptoms ofosteoarthritis of the knee. For the relief of such signs and symptoms,the recommended dose of diclofenac sodium topical solution, 1.5% (w/w),is 40 drops on each painful knee, 4 times a day.

Lidocaine hydrochloride topical solution is a local anesthetic agentindicated for the production of topical anesthesia of accessible mucousmembranes of the oral and nasal cavities and proximal portions of thedigestive tract. When used as a spray, or when applied by cottonapplicators or packs, as when instilled into a cavity, the suggesteddosage of Lidocaine Hydrochloride Topical Solution, 4%, is 1 to 5 mL (40to 200 mg lidocaine HCl), i.e., 0.6 to 3 mg/kg or 0.3 to 1.5 mg/lb. bodyweight. When spraying, the solution is to be transferred from itsoriginal container to an atomizer.

Lidocaine and prilocaine cream, 2.5%/2.5% is a eutectic mixture oflidocaine 2.5% and prilocaine 2.5% formulated as an oil in wateremulsion and is indicated for use on normal intact skin for localanalgesia and genital mucous membranes for superficial minor surgery andas pretreatment for infiltration anesthesia. The cream is applied tointact skin under occlusive dressing to provide dermal analgesia by therelease of lidocaine and prilocaine from the cream into the epidermaland dermal layers of the skin and by the accumulation of lidocaine andprilocaine in the vicinity of dermal pain receptors and nerve endings.

SUMMARY

In one aspect, a method of formulating a topical composition foradministration to a skin surface may include combining cannabidiolpowder and a cream including about 1.5% diclofenac sodium, about 2.5%lidocaine, and about 2.5% prilocaine.

In one example, combining the cannabidiol powder includes releasing thecannabidiol powder from a compounded capsule. In a further example,combining the cannabidiol powder with the cream includes combiningbetween about 10 mg and about 50 mg of the cannabidiol powder with thecream.

In another aspect, a method of formulating a topical composition foradministration to a skin surface includes combining between about 10 mgand about 50 mg cannabidiol powder, xylitol powder, and a solution,cream, gel, suspension, or ointment.

In one example, the method may include combining an NSAID, a localanesthetic, or combination thereof. The NSAID may include diclofenac andthe local anesthetic includes lidocaine, prilocaine, or both.

In one example, the method may include combining diclofenac, lidocaine,and prilocaine. The diclofenac may be combined in an amount betweenabout 0.5% and about 2% by weight of the topical composition, thelidocaine is combined in an amount between about 1.9% and about 3% byweight of the topical composition, and prilocaine is combined in anamount between about 1.9% and about 3% by weight of the topicalcomposition.

In one example, at least a portion of the cannabidiol powder and xylitolpowder are combined with the solution. The solution may include adiclofenac sodium, 1.5%, topical solution, lidocaine hydrochloride, 4%,topical solution, or both.

In one example, at least a portion of the cannabidiol powder and xylitolpowder are combined with the cream. In one formulation at least aportion of the cream includes lidocaine and prilocaine, 2.5%/2.5%,cream.

In any of the above examples, the cannabidiol powder includescannabidiol synthetic powder.

In one example, the cannabidiol powder is combined with the cream. Thecream may include about 1.5% diclofenac sodium, about 2.5% lidocaine,and about 2.5% prilocaine. The cream may further include between 5% and20% DMSO.

In still another aspect, a compounded capsule may include cannabidiolpowder and xylitol powder. In one example, the compounded capsule maycontain between about 10 mg and about 50 mg of the cannabidiol powder.The capsule may further include poloxamer powder. The poloxamer powdermay include poloxamer 407 and poloxamer 188. In a further example, thecompounded capsule may contain between about 10 mg and about 50 mg ofthe cannabidiol powder.

In yet another aspect, a method of providing pharmacological servicesincludes dispensing one or more capsules containing between about 10 mgand about 50 mg cannabidiol powder and xylitol powder for combining witha solution, cream, gel, suspension, or ointment prior to administrationof the combination to a skin surface.

In one example, the method may further includes dispensing the solution,cream, gel, suspension, or ointment.

DESCRIPTION

The present embodiments may relate to topically delivered or deliverablecompositions including topical solutions, suspensions, creams, gels, andlotions of medications for treatment of various ailments, such asinflammation or pain. In various embodiments the topical composition maycomprise compounded medications in a solution, suspension, cream, gel,ointment, or lotion format that may typically be topically administeredat a body surface, such as a surface of skin.

In various embodiments, the topical composition may include at least onecannabinoid including cannabidiol and a one or more of a non-steroidalanti-inflammatory drug (NSAID), local anesthetic, steroid, antibacterialdrug, antifungal drug, antiviral drug, anticonvulsant, orantidepressant. In one example, the topical composition comprises acannabinoid comprising at least cannabidiol and at least two activeagents including a local anesthetic and a NSAID. In one formulation, thelocal anesthetic comprises lidocaine, prilocaine, or both and the NSAIDcomprises diclofenac. In another formulation, the topical compositionincludes cannabidiol, lidocaine, and prilocaine and does not include aNSAID.

In one embodiment, the topical composition comprises cannabidiol andxylitol in a solution, cream, ointment, gel, or suspension. The topicalcomposition may be applied to the skin. In one example, a capsule or kitincluding a capsule containing cannabidiol powder and xylitol or anxylitol containing filler and base solution, cream, ointment, gel, orsuspension is provided for combining prior to administration. Thecapsule may include between about 5 mg and about 100 mg, such as betweenabout 10 mg and about 50 mg cannabidiol, corresponding to a unit dosagefor compounding with the base solution, cream, ointment, gel, orsuspension. In one example, the capsule contains cannabidiol andLOXASPERSE® for combining with a solution, cream, ointment, gel, orsuspension, and then applied to the skin. In another or a furtherexample, the topical composition includes additional active agents, suchas any described herein, such as local anesthetics, NSAIDS, analgesics,antidepressants, anticonvulsants, opioids, NMDA receptor antagonists,muscle relaxants, antifungals, antibiotics, antivirals, or combinationthereof. The additional active agents may be combined in amounts betweenabout 0.01% and 30% by weight individually and/or collectively. In oneexample, the additional active agents comprise diclofenac, lidocaine,and prilocaine in any amount or concentration described herein. In oneembodiment, the contents of the capsule is combined with a creamcontaining about 1.5% diclofenac sodium, about 2.5% lidocaine, and about2.5% prilocaine.

The topical composition may include all or some of the active agents ina powder and/or a commercially available medicated aqueous solution. Inone formulation, the topical composition comprises a compoundedformulation comprising cannabidiol and one or more commerciallyavailable medicated solutions comprising the NSAID and/or a localanesthetic and a commercially available medicated cream comprising oneor more local anesthetic. For example, the topical composition maycomprise a cannabidiol powder compounded with a NSAID solution and/or acommercially available local anesthetic solution compounded with acommercially available medicated cream comprising a local anesthetic.Such a topical composition may be stably formulated for topical deliveryto treat various ailments, such as inflammation or pain. The compoundedmedications may include topical solutions, emulsions, ointments, creams,lotions, or gels that may be topically administered at a body surfacewithin a solution, suspension, cream, gel, ointment, or lotion.

The topical composition may be formulated for effective administrationof multiple incorporated medications simultaneously for treatment of oneor more ailments may be provided. Ailments treated with the topicalcomposition may include, for example, conditions such as inflammation,rheumatoid arthritis, osteoarthritis, lateral epicondylitis (tenniselbow), medial epicondylitis (golfer's elbow), chondromalaciapatellae—CMP (runner's knee), tendonitis/carpel tunnel, soft tissuepain, fibromyalgia, diabetic neuropathy, peripheral neuropathy, neckpain, back pain, localized pain, plantar fasciitis, achilles tendonitis,tarsal tunnel—post-op massage, or heel pain. The topical composition mayexhibit excellent storage characteristics, and avoid separation and/ordegradation of the active ingredients in the aqueous environment forsubstantial lengths of time.

In some embodiments, the topical composition may include one or morecannabinoids and one or more local anesthetics and/or NSAIDs obtainedfrom commercially available solutions, commercially available creams,bulk powders, ground tablets, or combination thereof of including suchlocal anesthetics or NSAIDs. In one example, the one or morecannabinoids includes cannabidiol and less than 0.1%, such as less than0.01%, tetrahydrocannabinol. In a further example, the cannabidiol iscombined with the one or more local anesthetics and/or NSAIDs in apowder format. In a further example, the one or more local anestheticscomprise lidocaine and prilocaine and the one or more NSAIDs comprisediclofenac.

In various embodiments, the topical composition, which may include oneor more additional active agents selected from one or moreanticonvulsants, nerve depressants, muscle relaxants, NMDA(N-Methyl-D-aspartate) receptor antagonists, opiate or opioid agonists,antidepressants, and/or other active agents such as one or moresteroids, antibacterial drugs, antifungal drugs, antiviral drugs,anticonvulsants, or antidepressants.

In various embodiments, the cannabinoid may be selected fromcannabichromene (CBC), cannabichromevarin (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerovarin (CBCV), cannabigerol monomethyl ether (CBGM),cannabicyclol (CBL), cannabielsoin (CBE), cannabicitran (CBT),cannabinol (CBN), cannabivarin (CBV), tetrahydrocannabinol (THC),tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), orcombination thereof.

The cannabinoid may comprise cannabinoids within a whole plant extractor extract isolate, which may include one or more concentrated and/orsubstantially purified cannabinoids. In one embodiment, the cannabinoidcomprises a synthetic cannabinoid analogue, homologue, orpharmaceutically acceptable salt, derivative, variant, or combinationthereof. The amount of cannabinoid per gram of the topical compositionmay be between about 1 mg and about 100 mg. For example, per gram, thetopical composition may comprise cannabidiol in an amount between about2.5 mg and about 80 mg, about 2.5 mg and about 50 mg, about 2.5 mg andabout 25 mg, about 2.5 mg and about 20 mg, about 2.5 mg and about 15 mg,about 2.5 mg and about 10 mg, about 5 mg and about 50 mg, about 5 mg andabout 25 mg, about 5 g and about 15 mg, about 10 mg and about 50 mg,about 10 mg and about 25 mg, about 10 mg and about 15 mg, about 15 mgand about 80 mg, about 15 mg and about 50 mg, about 15 mg and about 25mg, about 25 mg and about 80 mg, about 25 mg and about 50 mg, or lessthat about 50 mg, less than about 25 mg, less than about 20 mg, lessthan about 15 mg, less than about 10 mg, less than about 5 mg, or lessthan about 2.5 mg.

In one embodiment, the cannabinoid comprises a synthetic cannabidiolanalogue, homologue, or pharmaceutically acceptable salt, derivative,variant, or combination thereof. In a further embodiment, thecannabidiol comprises a synthetic cannabidiol in a powdered format thatis dissolved or suspended in solution, cream, gel, ointment, or lotionto formulate the topical composition. In one example, the cannabidiolcomprises synthetic cannabidiol in a powder format having less than 1%,less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01% THCby weight.

As introduced above, the topical composition may include a cannabinoidand a NSAID. The NSAID may act to block the synthesis of prostaglandinsby inhibiting cyclooxygenase-2 and cyclooxygenase-1, for example. Invarious embodiments, the NSAID agent may be selected from one or moresalicylic acid derivatives (e.g., aspirin, diflunisal, salsalate,trilisate), one or more propionic acids (e.g., flurbiprofen, ibuprofen,ketoprofen, naproxen, oxaprozin), one or more acetic acids (e.g.,diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac,tolmetin), one or more fenamates (e.g., meclofenamate), one or moreoxicams (meloxicam, piroxicam), or one or more COX-2 inhibitors (e.g.,celecoxib, rofecoxib, valdecoxib), or combinations thereof. For example,in one embodiment, the NSAID agent comprises a benzeneacetic acidderivative such as diclofenac or pharmaceutically acceptable saltthereof, which in one example is provided in an aqueous solution.

As introduced above, the topical composition may include a diclofenactopical solution comprising diclofenac in an aqueous solution. Thediclofenac topical solution may be a commercially available diclofenactopical solution, such as diclofenac sodium solution for topicaladministration. The diclofenac sodium solution may contain, for example,1.5% (w/w), diclofenac sodium wherein each 1 mL of solution containsabout 16.05 mg of diclofenac sodium. In one embodiment, the diclofenacsolution comprises a diclofenac sodium solution, 1.5% (w/w), such asthat which is manufactured under the trade name PENNSAID® by NuvoManufacturing, Varennes, Quebec, Canada or Diclofenac Sodium TopicalSolution, 1.5% (w/w), manufactured by Apotex Inc. Toronto, Ontario,Canada M9L 1T9 for Apotex Corp. Weston, Fla. 33326 for treating the painof osteoarthritis of the knee. The diclofenac solution may also containvarious inactive ingredients such as dimethyl sulfoxide USP (DMSO, 45.5%w/w), ethanol, glycerin, propylene glycol and purified water. In oneembodiment, the diclofenac solution comprises a diclofenac sodiumsolution marketed under the trade name PENNSAID® and manufactured byNuvo Manufacturing, Varennes, Quebec, Canada, in a 2% (w/w) diclofenacsolution for treating the pain of osteoarthritis of the knee. Each gramof solution may contain about 20 mg of diclofenac sodium and variousinactive ingredients such as dimethyl sulfoxide USP (DMSO, 45.5% w/w),ethanol, purified water, propylene glycol, and hydroxypropyl cellulose.In other embodiments, other concentrations of diclofenac solution, suchas diclofenac sodium solutions, may be used.

In various embodiments, the topical composition may comprise diclofenacsodium topical solution, 1.5% (w/w), in an amount between about 0.1 gand about 0.8 g per gram. For example, the topical composition maycomprise between about 0.1 g and about 0.7 g, about 0.1 g and about 0.6g, about 0.1 g and about 0.5 g, about 0.1 g and about 0.4 g, about 0.1 gand about 0.3 g, about 0.1 g and about 0.3 g, about 0.2 and about 0.8,about 0.2 g and about 0.7 g, about 0.2 g and about 0.6 g, about 0.2 gand about 0.5 g, about 0.2 g and about 0.4 g, about 0.2 and about 0.3 g,about 0.3 and about 0.8, about 0.3 g and about 0.7 g, about 0.3 g andabout 0.6 g, about 0.3 g and about 0.5 g, about 0.3 g and about 0.4 g,about 0.4 and about 0.8, about 0.4 g and about 0.7 g, about 0.4 g andabout 0.6 g, about 0.4 g and about 0.5 g, about 0.5 g and about 0.6 g,about 0.5 g and about 0.7 g, about 0.5 g and about 0.8 g, or greaterthan or equal to about 0.1 g, about 0.2 g, about 0.3 g, about 0.4 g,about 0.5 g, about 0.6 g, about 7 g, or about 0.8 g, or less than orequal to about 0.8 g, about 0.7 g, about 0.6 g, about 0.5 g, about 0.4g, about 0.3 g, about 0.2 g, or about 0.1 g diclofenac sodium topicalsolution, 1.5% (w/w), per gram of topical composition. In one example,the topical composition comprises about 0.1 g, about 0.2 g, about 0.3 g,about 0.4 g, about 0.5 g, about 0.6 g, about 0.7 g, or about 0.8 gdiclofenac sodium topical solution, 1.5% (w/w), per gram.

In various embodiments, the topical composition may include diclofenacbulk powder, such as diclofenac sodium or diclofenac potassium bulkpowder. In a further or another example, the topical compositionincludes crushed diclofenac sodium tablets for oral administrationcontaining diclofenac sodium. The tablets may also include one or moreof aluminum hydrate, colloidal silicon dioxide, hypromellose, lactosemonohydrate, magnesium stearate, microcrystalline cellulose,polyethylene glycol, polysorbate 80, polyvinyl acetate phthalate,propylene glycol, silica, sodium alginate, sodium starch glycolate (TypeA), stearic acid, synthetic black iron oxide, talc, or titanium dioxide.In a further or another example, the topical composition includesdiclofenac sodium topical gel including diclofenac sodium. Diclofenacsodium topical gel may also contain one or more of carbomer homopolymerType C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineraloil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, orstrong ammonia solution. Diclofenac sodium topical gel may be availableas Diclofenac Sodium Topical Gel, 1% w/w. In an above or furtherexample, the topical composition may include diclofenac potassium fororal solution containing diclofenac potassium and which is available asa flavored soluble powder that is designed to be mixed with water priorto oral administration. In an above or further example, the topicalcomposition may include diclofenac potassium tablets for oraladministration containing diclofenac potassium and which may alsocontain one or more of colloidal silicon dioxide, corn starch, FD&C BlueNo. 2, FD&C Red No. 40, FD&C Yellow No. 6, hypromellose, lactosemonohydrate, magnesium stearate, microcrystalline cellulose,polyethylene glycol 4000, povidone, sodium starch glycolate, titaniumdioxide, or tricalcium phosphate.

In some methods, diclofenac sodium topical solution, 1.5% (w/w), orequivalent is compounded in an amount between about 0.1 g and about 0.8g per gram or in a lesser amount sufficient to provide between about 1.6mg and about 20 mg of the diclofenac sodium present in one gram of thetopical composition alone or together with one or more additionaldiclofenac sources, e.g. bulk powder or ground tablets. For example,diclofenac bulk powder, ground tablets, and/or diclofenac sodium topicalsolution, 1.5% (w/w), may be added in an amount sufficient to providebetween 1.6 mg and about 20 mg, about 5 mg and about 16 mg, about 5 mgand about 15 mg, about 7 mg and about 15 mg, about 7 mg and about 10 mg,about 10 mg and about 20 mg, about 15 mg and about 20 mg, about 1.6 mgand about 12 mg, about 2 mg and about 10 mg, about 2 mg and about 9 mg,about 2 mg and about 8 mg, about 2 mg and about 7 mg, about 2 mg andabout 6 mg, about 2 mg and about 5 mg, about 2 mg and about 4 mg, about2 mg and about 3 mg, about 3 mg and about 9 mg, about 3 mg and about 8mg, about 3 mg and about 7 mg, about 3 mg and about 6 mg, about 3 mg andabout 5 mg, about 4 mg and about 12 mg, about 4 mg and about 11 mg,about 4 mg and about 10 mg, about 4 mg and about 9 mg, about 4 mg andabout 8 mg, about 4 mg and about 7 mg, about 4 mg and about 6 mg, about4 mg and about 5 mg, about 5 mg and about 12 mg, about 5 mg and about 11mg, about 5 mg and about 10 mg, such as greater than or equal to about 1mg, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about12 mg, about 14 mg, about 16 mg, about 18 mg, or about 20 mg, or lessthan or equal to about 1 mg, about 2 mg, about 4 mg, about 6 mg, about 8mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, orabout 20 mg or greater diclofenac or diclofenac sodium present in onegram of the topical composition.

The local anesthetic agent may comprise one or more local anestheticsselected from lidocaine, prilocaine, benzocaine, or combination thereof.All or a portion of the local anesthetic agent may be provided in acommercially available aqueous solution. Additionally or alternatively,all or a portion of the local anesthetic agent may be provided by acommercially available medicated cream (e.g., cream, hydrous ointment,gel, lotion, emulsion) or anhydrous ointment. In some of the aboveembodiments or another embodiment, the local anesthetic agent mayinclude bulk powder, ground oral tablets, or both. For example, an NSAIDtopical solution may include a commercially available diclofenac, orpharmaceutically acceptable salt thereof, topical solution and a localanesthetic topical solution may include a commercially availablelidocaine, or pharmaceutically acceptable salt thereof, topicalsolution. In embodiments including one or more additional NSAIDs, localanesthetics, or both, additional actives may be provided in commerciallyavailable solutions, creams, or bulk/pure powders or crushed commercialtablets and then combined with the topical composition or a componentthereof. For example, one or more additional local anesthetic and/orNSAID actives may be provided in a solution, cream, ointment, bulk/purepowder, or crushed commercial tablet and then combined with the topicalcomposition or a component thereof. The topical composition may also besupplemented with creams, bulk/pure powders, or crushed commercialtablets comprising an NSAID and/or local anesthetic that is also presentin a commercial topical solution compounded to formulate the topicalcomposition.

In various embodiments, the topical composition may include a lidocainetopical solution comprising lidocaine in an aqueous solution. Thelidocaine topical solution may be a commercially available lidocainetopical solution, such as lidocaine hydrochloride solution for topicaladministration. The lidocaine hydrochloride solution may contain, forexample, 4% lidocaine (w/v) wherein each mL includes 40 mg lidocaineHC1. For example, in one embodiment, the lidocaine topical solution maybe Lidocaine Hydrochloride Topical Solution USP, 4% manufactured by IGILabs, Inc., Buena, New Jersey, in 50 mL screw cap glass bottles. Thelidocaine hydrochloride topical solution may contain various inactiveingredients such as methylparaben, purified water, and sodium hydroxideto adjust pH to 6.0-7.0.

In one embodiment, the topical composition includes lidocaine bulkpowder, such as lidocaine hydrochloride USP monohydrate powder inaddition to or instead of lidocaine topical solution. Lidocainehydrochloride USP monohydrate powder includes 1 g of lidocaine per 1.23g.

Prilocaine is another local anesthetic drug that may be compounded withthe cannabinoid, e.g., cannabidiol, NSAID, and/or another localanesthetic to formulate the topical composition, which, in one example,may be compounded at least in part from one or more topical solutionssuch as diclofenac topical solution and/or lidocaine topical solution.Prilocaine may be compounded from prilocaine hydrochloride USP powder.Prilocaine hydrochloride USP powder includes 1 g of prilocaine per 1.165g. In some embodiments, prilocaine may be compounded from PrilocaineHydrochloride Injection, USP, 4%, which is a sterile, non-pyrogenicisotonic solution that contains prilocaine HC1 40 mg/mL at a pH of 6.0to 7.0 and is designed to be administered parenterally by injection. Inan above or another embodiment, prilocaine may be compounded fromPrilocaine Hydrochloride 4% with epinephrine injection, which is asterile, non-pyrogenic isotonic solution that contains prilocaine withepinephrine (as bitartrate) and is administered parenterally byinjection. The injection solution is available as prilocaine epinephrine1:200,000, containing prilocaine HC1 40.0 mg/mL, epinephrine 0.005mg/mL, citric acid 0.2 mg/mL, and sodium metabisulfite 0.5 mg/mL and hasa pH of 3.3 to 5.5.

The topical composition may be formulated by compounding one or more ofthe actives with a commercially available medicated composition, such asa solution, cream, or ointment, comprising two or more actives. Forexample, the topical composition may include a lidocaine and prilocainecream. In one example, the topical composition includes Lidocaine 2.5%and Prilocaine 2.5% Cream, USP, (or Lidocaine and Prilocaine 2.5%/2.5%Cream) which is an emulsion in which the oil phase is a eutectic mixtureof lidocaine and prilocaine in a ratio of 1:1 by weight. This eutecticmixture has a melting point below room temperature and therefore bothlocal anesthetics exist as a liquid oil rather than as crystals. It ispackaged in 5 gram and 30 gram tubes. Each gram of lidocaine andprilocaine cream contains lidocaine 25 mg, prilocaine 25 mg,polyoxyethylene fatty acid esters (as emulsifiers) such asPEG-60/hydrogenated castor oil, carboxypolymethylene (as a thickeningagent) such as carbomer 934P, carbopol 5984, sodium hydroxide to adjustto a pH approximating 9, and purified water to 1 gram. Lidocaine 2.5%and Prilocaine 2.5% Cream, USP, is currently manufactured by TeligentPharma, Inc., Buena, N.J. 08310 USA, for distribution by Actavis Pharma,Inc., Parsippany, N.J. 07054 USA. Lidocaine and prilocaine cream,2.5%/2.5%, is also manufactured and distributed by other sources such asE. Fougera & Co. a division of Fougera Pharmaceuticals Inc., Melville,N.Y. 11747.

In some embodiments, the topical composition includes a commerciallyavailable lidocaine and prilocaine periodontal gel, such as PeriodontalGel, 2.5%/2.5%, which is a microemulsion in which the oil phase is aeutectic mixture of lidocaine and prilocaine in a ratio of 1:1 byweight. This eutectic mixture has a melting point below roomtemperature; therefore, both local anesthetics exist as liquid oilsrather than as crystals. Lidocaine and Prilocaine Gel 2.5%/2.5% iscurrently available under ORAQIX® (manufactured for DentsplyPharmaceutical, York, Pa. 17404) in single-use glass cartridges thatdeliver up to 1.7 g (1.7 mL) of gel (42.5 mg of lidocaine and 42.5 mg ofprilocaine). In various embodiments described herein including lidocaineand prilocaine cream, 2.5%/2.5%, lidocaine and prilocaine cream,2.5%/2.5%, may be replaced in whole or in-part with Lidocaine andPrilocaine Gel 2.5%/2.5%.

In some embodiments, the topical composition comprises a topicalsolution portion comprising diclofenac sodium topical solution, 1.5%(w/w), and lidocaine hydrochloride topical solution, 4%. The topicalcomposition may further comprise a lidocaine and prilocaine cream orgel, 2.5%/2.5% portion. The topical composition may also comprise apowder portion comprising cannabidiol, diclofenac, lidocaine,prilocaine, or combination thereof. The powder portion may comprise bulkpowder or ground oral tablets. The powder portion may comprisepharmaceutically acceptable salts of the active agents, such as thoseidentified herein. In some embodiments, the cannabidiol comprises asynthetic cannabidiol. The synthetic cannabidiol may be synthesized fromD-limonene. The cannabidiol powder may comprise synthetic Cannabidiol(>98% Powder).

In one embodiment, the topical composition comprises a commerciallyavailable topical solution portion comprising a lidocaine hydrochloridesolution and/or a diclofenac sodium solution and a lidocaine andprilocaine cream or gel, 2.5%/2.5% portion. For example, the topicalcomposition may comprise a diclofenac sodium topical solution andlidocaine and prilocaine cream, 2.5%/2.5%. In another example, thetopical composition comprises a commercially available diclofenac sodiumsolution, a commercially available lidocaine hydrochloride solution, andcommercially available lidocaine and prilocaine cream, 2.5%/2.5%. Inanother or a further example, the topical composition comprisesdiclofenac sodium USP powder, lidocaine hydrochloride USP monohydratepowder, prilocaine hydrochloride USP powder, or combination thereof. Theactives present in one or more bulk powders may also be replaced orsupplemented with powder obtained from ground oral tablets comprisingthe actives. The bulk powder or ground oral tablets may comprisepharmaceutically acceptable salts of the active agents, such as thoseidentified herein. The commercially available diclofenac sodium solutionmay be diclofenac sodium topical solution, 1.5% (w/w). The lidocainehydrochloride solution may be lidocaine hydrochloride topical solution,4%. The cannabidiol may comprise a synthetic cannabidiol powder. Thesynthetic cannabidiol may be synthesized from D-limonene and comprisesynthetic Cannabidiol (>98% Powder).

In various embodiments, the topical composition formulated by combininga lidocaine hydrochloride topical solution, powder, cream, or ointmentand diclofenac sodium topical solution or powder in relatively lowconcentrations of the active ingredients compared to conventionaltopical formulations including one or more of the active ingredients.Due to the formulation and combination described herein, the presenttopical composition may provide similar effectiveness while having anincreased safety profile. The increased safety profile may be especiallybeneficial to patients with gastric bleeds, on blood thinners, etc. Theprovision of cannabidiol, e.g., synthetic powder, compounded with thelidocaine and diclofenac may address pain and/or inflammation. Thecompounded composition may also provide local anesthetic benefits whilepromoting deeper penetration into the skin and leveraging DMSO into thecompounded topical cream, e.g., 45.5% (w/w) of the diclofenac sodiumsolution compounded with the lidocaine, such as lidocaine hydrochloridesolution.

In various embodiments, the topical composition comprises a topicalsolution, suspension, cream, ointment, or gel including cannabidiol at aconcentration between about 0.1% and about 25%, diclofenac or diclofenacsodium at a concentration between about 0.1% and about 1.9% andlidocaine or lidocaine hydrochloride at a concentration of between about0.1% and about 4%. In a further example, the topical composition mayinclude prilocaine at a concentration between about 0.1% and about 4%.In one example, the topical composition includes about 0.5% or more,about 2% or more, about 7% or more, about 10% of more, or about 17% ormore cannabidiol, about 0.5% or more, about 1.0% or more, about 1.25% ormore, or between about 1.1% and 3% diclofenac or diclofenac sodium, andabout 1% or more, about 2% or more, about 3% or more, or about 4% ormore lidocaine or lidocaine hydrochloride. In a further example, thetopical composition may include prilocaine at a concentration betweenabout 0.1% and about 4%, such as about 1% or more, about 2% or more, orabout 3% or more. In one example, the topical composition comprisesbetween about 2% and about 17% cannabidiol, between about 1.15% andabout 1.6% diclofenac, and between about 1.9% and about 2.75% of each oflidocaine and prilocaine by weight. As used herein, the term about means+/−10% of the stated value it modifies. In some embodiments, the topicalcomposition comprising a topical solution or suspension includingbetween about 0.5% and about 20%, about 1.5% and about 17%, about 2.5%and about 17%, about 2% and about 20%, about 2% and about 17%, about 2%and about 15%, about 2% and about 10%, about 2% and about 7%, about 10%and about 20%, or about 10% and about 15%, cannabidiol by weight,between about 1.0% and about 2%, about 1.1% and about 1.8%, about 1.2%and about 1.7%, about 1.2% and about 1.6%, about 1.2% and about 1.5%,about 1.2% and about 1.4%, about 1.2% and about 1.3%, about 1.3% andabout 1.6%, about 1.3% and about 1.5%, about 1.3% and about 1.4%, about1.4% and about 1.6%, about 1.4% and about 1.5% diclofenac or diclofenacsodium, and between about 0.2% and about 0.8%, about 0.2% and about0.7%, about 0.2% and about 0.6%, about 0.2% and about 0.5%, about 0.2%and about 0.4%, about 0.2% and about 0.3%, about 0.3% and about 0.7%,about 0.3% and about 0.6%, about 0.3% and about 0.5%, about 0.3% andabout 0.4%, about 0.330% and about 0.340%, about 1.0% and about 4%,about 1% and about 3%, about 1% and about 2%, about 2% and about 4%,about 3% and about 4% lidocaine or lidocaine hydrochloride. In a furtherembodiment, the topical solution includes between about 0.2% and about40%, about 1.0% and about 4%, about 1% and about 3%, about 1% and about2%, about 2% and about 4%, or about 3% and about 4% prilocaine. Forexample, in various embodiments, the topical solution comprises betweenabout 0.5% and about 10% cannabidiol, about 1.0% and about 2.0%, such asbetween about 1.3% and about 1.6%, diclofenac sodium, and between about0.1% and about 0.5%, such as between about 0.3% and about 0.35%,lidocaine hydrochloride. In one embodiment, the topical solutionincludes between about 0.5% and about 20%, such as between about 2% andabout 17% cannabidiol, between about 1.25% and about 1.47% diclofenacsodium, and between about 1.9% and about 2.45% of each of prilocaine orprilocaine hydrochloride and lidocaine or lidocaine hydrochloride. Inanother embodiment, the topical solution includes between about 2% andabout 20% cannabidiol, about 1.5% diclofenac, about 2.5% lidocaine, andabout 2.5% prilocaine by weight. In various embodiments, a method offormulating the topical composition includes combining between about0.5% and about 20% cannabidiol synthetic powder, a commerciallyavailable diclofenac sodium solution, diclofenac sodium topicalsolution, 1.5% (w/w), or diclofenac sodium topical solution 2.0% (w/w)solution, and a commercially available lidocaine solution, such aslidocaine hydrochloride topical solution, 4%, to formulate the topicalcomposition having one of the above listed concentrations or otherconcentration described herein of cannabidiol, diclofenac sodium, andlidocaine hydrochloride. In some embodiments, the topical compositioncomprises a topical solution as above with prilocaine at a concentrationbetween about 1:2 and 2:1 of that of lidocaine. Stronger or weakerconcentrations of diclofenac or diclofenac sodium topical solutions andlidocaine or lidocaine hydrochloride topical solutions may be usedwherein the amounts of such solutions added are modified to achieve theappropriate concentrations. In some embodiments, the concentrations oramounts of diclofenac and lidocaine may be provided by compoundingpowders, crushed tablets, creams, ointments, gels, other formats inaddition to or instead of diclofenac sodium solution and lidocainehydrochloride solution.

In various embodiments, the topical composition comprises cannabidiol inany amount or concentration described herein and a commerciallyavailable diclofenac sodium topical solution, 1.5% (w/w), compoundedwith a commercially available lidocaine hydrochloride topical solution,4%, wherein the topical composition includes diclofenac sodium topicalsolution, 1.5% (w/w), at a concentration between 0.1% and 99%, such asbetween 50% and 95%, (v/v) and lidocaine hydrochloride topical solution,4%, at a concentration between 0.1% and 90%, such as 0.2% and 5%, (v/v).In one example, the topical composition includes about 80% or more,about 90% or more, or about 91.7% (v/v) diclofenac sodium topicalsolution, 1.5% (w/w), and about 4% or more, about 7% or more, or about8.32% (v/v) lidocaine hydrochloride topical solution, 4%. In oneembodiment, the topical composition includes about 90% (v/v) diclofenacsodium topical solution, 1.5% (w/w), and about 10% (v/v) lidocainehydrochloride topical solution, 4%. In some embodiments, the topicalcomposition includes between about 50% and about 98%, about 55% andabout 97%, about 60% and about 96%, about 70% and about 95%, about 80%and about 95%, about 85% and about 95%, about 90% and about 95%, about90% and about 94%, about 90% and about 93%, about 90% and about 92%,about 91% and about 93%, about 91% and about 92% (v/v) diclofenac sodiumtopical solution, 1.5% (w/w), and between about 2% and about 20%, about4% and about 18%, about 6% and about 16%, about 6% and about 16%, about6% and about 12%, about 6% and about 10%, about 7% and about 14%, about7% and about 12%, about 7% and about 10%, about 8% and about 14%, about8% and about 12%, about 8% and about 10% (v/v) lidocaine hydrochloridetopical solution, 4%. For example, in various embodiments, the topicalcomposition comprises between about 80% and about 95%, such as betweenabout 90% and about 93% (v/v) diclofenac sodium topical solution, 1.5%(w/w), and between about 4% and about 14%, such as between about 7% andabout 10% (v/v) lidocaine hydrochloride topical solution, 4%. In oneembodiment, the topical composition includes about 91.7% diclofenacsodium topical solution and about 8.32% lidocaine hydrochloride topicalsolution, 4%. In various embodiments, a method of formulating thetopical composition includes combining a commercially availablediclofenac sodium solution, such as diclofenac sodium topical solution,1.5% (w/w), with a commercially available lidocaine solution, such aslidocaine hydrochloride topical solution, 4%, to form a topicalcomposition having one of the above listed concentrations (v/v) ofdiclofenac sodium topical solution, 1.5% (w/w), and lidocainehydrochloride topical solution, 4%. In some embodiments, the topicalcomposition comprises a topical solution as above further includingprilocaine at a concentration between about 1:2 and 2:1 of that oflidocaine. Stronger or weaker concentrations of diclofenac or diclofenacsodium topical solutions and lidocaine or lidocaine hydrochloridetopical solutions may be used wherein the amounts of such solutionsadded are modified to achieve the appropriate v/v concentrations.

In any embodiment described herein, the topical composition may includexylitol and/or poloxamer. Xylitol may be present in a weight percentbetween about 0.1% and about 5% or in another weight percent describedabove or elsewhere herein. Poloxamers may be present in a weight percentbetween about 0.1% and about 5% by weight. In one embodiment, the one ormore poloxamers comprise poloxamer 407 and poloxamer 188. For example, amethod of making the topical composition may include combining thecontents of a capsule comprising cannabidiol powder and xylitol and/orpoloxamer with a aqueous solution, cream, gel, ointment, lotion, oremulsion. The additional actives may be within the solution, cream, gel,ointment, lotion, or emulsion or may be combined with the same toformulate the topical composition.

In further or other embodiments, the method may also include combiningcannabidiol in an amount described herein and one or more additionalactive agents comprising one or more NSAIDs selected from salicylic acidderivatives (e.g., aspirin, diflunisal, salsalate, trilisate), one ormore propionic acids (e.g., flurbiprofen, ibuprofen, ketoprofen,naproxen, oxaprozin), one or more acetic acids (e.g., etodolac,indomethacin, ketorolac, nabumetone, sulindac, tolmetin), one or morefenamates (e.g., meclofenamate), one or more oxicams (meloxicam,piroxicam), or one or more COX-2 inhibitors (e.g., celecoxib, rofecoxib,valdecoxib), or combinations thereof, one or more local anestheticsselected from prilocaine, benzocaine, or combination thereof, one ormore muscle relaxants selected from baclofen, carisoprodol,orphenadrine, cyclobenzaprine, dantrolene, tizanidine, amitriptyline, orcombinations thereof, one or more NMDA receptor antagonists such asketamine, or one or more opioid or opiate agonists selected fromoxycodone, morphine, fentanyl, hydrocodone, codeine, butalbital,tramadol, or combinations thereof, one or more nerve depressantsselected from gabapentin, topiramate, lamotrigine, or combinationsthereof, and/or other active agents. In one embodiment, the topicalcomposition includes one or more additional active agents selected fromone or more antibiotics, antifungals, or antivirals. However, someembodiments may exclude additional active agents. The additional activeagents may be provided in powder form (e.g., pure powder or crushedtablets), suspension, gel, solution, or cream, e.g., emulsion. In someembodiments, each additional active agent may be added to 0.1% to 5% byweight of the topical composition.

In some embodiments, the topical composition comprises a topical paincream, which may include an ointment, gel, or emulsion, comprisingcannabidiol. In one example, the topical pain cream comprises at leasttwo commercially available topical solutions that are compoundedtogether. For example, the topical composition may include acommercially available NSAID topical solution and a commerciallyavailable local anesthetic topical solution as described herein. Theactives may be compounded with a base cream, gel, ointment, lotion, oremulsion. The topical composition may also comprise medicated creams,lotions, gels, ointments, pastes, tablets, bulk powders, or othermedicated formats including all or a portion of one or more of theactive agents. Thus, the topical composition may include cannabidiol, alocal anesthetic agent comprising one or more local anesthetics, and anNSAID agent comprising one or more NSAIDs obtained from commerciallyavailable solutions, creams, lotions, gels, ointments, pastes, groundoral tablets, or combination thereof. Some embodiments may also includebulk powders in addition to or instead of commercially availablesolutions, creams, lotions, gels, ointments, pastes, ground oraltablets, or combination thereof. For example, the topical compositionmay comprise at least two commercially available medicated topicalsolutions, a commercially available medicated topical cream (which mayinclude a cream, hydrous ointment, lotion, gel, or emulsion) oranhydrous ointment, and one or more actives comprising bulk powder orground tablets.

In some embodiments, the topical composition described anywhere hereinmay further include xylitol and/or one or more poloxamers. Xylitol maybe present in a weight percent between about 0.1% and about 5% or inanother weight percent described above or elsewhere herein. Poloxamersmay be present in a weight percent between about 0.1% and about 5% byweight. In one embodiment, the one or more poloxamers comprise poloxamer407 and poloxamer 188.

The topical composition may exhibit excellent storage characteristics,and avoid separation and/or degradation of the active ingredients forsubstantial lengths of time. As noted above, the composition may be in acream format comprising an aqueous phase and an oil phase. In variousembodiments, active ingredients in a topical cream preparation may be inthe aqueous phase, oil phase, or both.

As introduced above and elsewhere herein, the topical composition mayinclude a diclofenac, such as diclofenac sodium topical solution, 1.5%(w/w), compounded with lidocaine and prilocaine cream, 2.5%/2.5%. Invarious embodiments, the topical composition may comprise lidocaine andprilocaine cream, 2.5%/2.5%, in an amount between about 0.2 g and about0.7 g per gram. For example, the topical composition may comprisebetween about 0.2 g and about 0.7 g, about 0.2 g and about 0.6 g, about0.2 g and about 0.5 g, about 0.2 g and about 0.4 g, about 0.2 and about0.3 g, about 0.3 g and about 0.7 g, about 0.3 g and about 0.6 g, about0.3 g and about 0.5 g, about 0.3 g and about 0.4 g, about 0.4 g andabout 0.7 g, about 0.4 g and about 0.6 g, about 0.4 g and about 0.5 g,about 0.5 g and about 0.6 g, about 0.5 g and about 0.7 g, about 0.6 gand about 0.9 g or greater than or equal to about 0.1 g, about 0.2 g,about 0.3 g, about 0.4 g, about 0.5 g, about 0.7 g, or about 9 g or lessthan or equal to about 0.9 g, about 0.7 g, about 0.5 g, about 0.4 g,about 0.3 g, about 0.2 g, or about 0.1 g lidocaine and prilocaine cream,2.5%/2.5%, per gram of topical composition. In one example, the topicalcomposition comprises about 0.1 g, about 0.2 g, about 0.3 g, about 0.4g, about 0.5 g, about 0.7 g, or about 0.9 g lidocaine and prilocainecream, 2.5%/2.5%, per gram. In one embodiment, the topical compositioncomprises between about 0.5 and about 0.9 g lidocaine and prilocainecream, 2.5%/2.5%, per gram.

In some methods, commercially available lidocaine and prilocaine cream,2.5%/2.5%, is compounded in an amount between about 0.2 g and about 0.7g per gram or in a lesser amount together with lidocaine and prilocainefrom other sources sufficient to provide between about 5 mg and about 40mg of each of the lidocaine and prilocaine present in one gram of thetopical composition. For example, lidocaine and prilocaine cream,2.5%/2.5%, may be added in an amount sufficient to provide between about5 mg and about 23 mg, about 5 mg and about 15 mg, about 5 mg and about14 mg, about 5 mg and about 12 mg, about 5 mg and about 11 mg, about 5mg and about 10 mg, about 5 mg and about 9 mg, about 5 mg and about 8mg, about 5 mg and about 6 mg, about 6 mg and about 16 mg, about 6 mgand about 15 mg, about 6 mg and about 14 mg, about 6 mg and about 12 mg,or about 6 mg and about 22 mg of each of the lidocaine and prilocainepresent in one gram of the topical composition. In some embodiments, theamounts of each of lidocaine and prilocaine per gram of the topicalcomposition provided by lidocaine and prilocaine cream, 2.5%/2.5%, isabout 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg,about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 13mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, or about 23 mg.In some embodiments, the amount of lidocaine and/or prilocaine isgreater than or equal to about 2.5%. Thus, the topical composition maybe formulated to include 25 mg or greater of one or both of lidocaineand prilocaine per gram. In some such embodiments, lidocaine solution orpowder and/or prilocaine powder may be used in addition to or instead oflidocaine and prilocaine cream 2.5%/2.5%.

As introduced above and elsewhere herein, the topical composition maycomprise cannabidiol and lidocaine hydrochloride topical solution suchas commercially available lidocaine hydrochloride topical solution, 4%,compounded with commercially available diclofenac sodium topicalsolution, 1.5% (w/w), and/or commercially available lidocaine andprilocaine cream, 2.5%/2.5%. The topical composition may includecannabidiol in an amount between about 2.5 mg and about 100 mg, such asbetween about 2.5 mg and about 50 or between about 4 mg and about 35 mgper gram and lidocaine hydrochloride topical solution, 4%, in an amountbetween 0 and about 0.5 g per gram. For example, the topical compositionmay comprise lidocaine hydrochloride topical solution, 4%, or equivalentin an amount between about 0.001 g and about 0.01 g, about 0.005 g andabout 0.02 g, about 0.009 g and about 0.02 g, about 0.09 g and about0.01 g, about 0.01 g and about 0.02, about 0.01 g and about 0.1 g, about0.1 g and about 0.4 g, about 0.1 g and about 0.3 g, about 0.1 g andabout 0.2 g, about 0.2 and about 0.3 g, about 0.3 and about 0.5, about0.3 g and about 0.4 g, or greater than or equal to about 0.001 g, about0.01 g, about 0.02 g, about 0.05 g, about 0.1 g, about 0.2 g, about 0.3g, or about 0.4 g, or less than or equal to about 0.001 g, about 0.01 g,about 0.02 g, about 0.05 g, about 0.1 g, about 0.2 g, about 0.3 g, orabout 0.4 g lidocaine hydrochloride topical solution, 4%, per gram oftopical composition. In one example, the topical composition comprisesabout 0.001 g, about 0.01 g, about 0.02 g, about 0.05 g, about 0.1 g,about 0.2 g, about 0.3 g, or about 0.4 g lidocaine hydrochloride topicalsolution, 4%, per gram.

In some methods, lidocaine hydrochloride topical solution, 4%, iscompounded in an amount between 0 g and about 0.7 g per gram of thetopical composition or in an amount sufficient to provide between about1 mg and about 25 mg of the lidocaine present in one gram of the topicalcomposition. For example, lidocaine hydrochloride topical solution, 4%,may be added in an amount sufficient to provide between about betweenabout 0.01 mg and about 0.1 mg, about 0.1 mg and about 3 mg, about 0.1mg and about 2 mg, about 0.1 mg and about 1 mg, about 0.1 mg and about0.8 mg, about 0.1 mg and about 0.6 mg, about 0.2 mg and about 0.8 mg,about 0.2 mg and about 0.6 mg, about 0.2 mg and about 0.5 mg, about 0.2mg and about 0.4 mg, about 0.2 mg and about 0.3 mg, about 0.3 mg andabout 0.8 g, about 0.3 mg and about 0.6 mg, about 0.3 mg and about 0.5mg, about 0.3 mg and about 0. 4 mg, about 0.4 mg and about 0.8 mg, about0.4 mg and about 0.6 mg, about 0. 6 mg and about 0.8 mg, about 0.8 mgand about 2 mg, about 1 mg and about 25 mg, about 3 mg about 15 mg,about 3 mg and about 10 mg, about 5 mg and about 15 mg, about 5 mg andabout 10 mg, about 10 mg and about 15 mg, about 15 mg and about 25 mg orgreater than or equal to about 0.1 mg, about 0.2 mg, about 0.3 mg, about0.4 mg, about 0.5 mg, about 0.6 mg, about 0.8 mg, or about 0.9 mg, about1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg orless than or equal to about 0.1 mg, about 0.2 mg, about 0.3 mg, about0.4 mg, about 0.5 mg, about 0.6 mg, about 0.8 mg, or about 0.9 mg, about1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mglidocaine per gram of topical composition. In some embodiments, theamount of lidocaine per gram of the topical composition provided bylidocaine hydrochloride topical solution, 4%, is about 0.1 mg, about 0.5mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, orabout 25 mg.

As introduced above and elsewhere herein, in some embodiments, thecompounded composition may comprise cannabidiol synthetic powder,diclofenac sodium topical solution, 1.5% (w/w), lidocaine and prilocainecream, 2.5%/2.5%, and lidocaine and/or prilocaine bulk powder. Someembodiments may further include lidocaine hydrochloride topicalsolution, 4%. The topical composition may include between 0 mg and about50 mg of each of lidocaine and prilocaine or pharmaceutically acceptablesalt or equivalent thereof. For example, the topical composition maycomprise between 0 and 50 mg per gram such as between about 1 mg andabout 10 mg, about 5 mg and about 15 mg, about 10 mg and about 20 mg,about 15 mg and about 25 mg, about 20 mg and about 30 mg, about 25 mgand about 35 mg, about 30 mg and about 40 mg, about 35 mg and about 45mg, about 40 mg and about 50 mg, about 5 mg and about 25 mg, about 5 mgand about 30 mg, about 5 mg and about 45 mg, or greater than or equal toabout 1 mg, about 3 mg, about 5 mg, about 6 mg, about 8 mg, about 9 mg,about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about16 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, or less than or equal to about 3 mg, about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, or about 50 mg per gram of topicalcomposition. In an example, the topical composition includes about 1 mg,about 3 mg, about 5 mg, about 6 mg, about 8 mg, about 9 mg, about 10 mg,about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 16 mg, about20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,or about 50 mg of lidocaine per gram of the topical composition frombulk powders such as hydrochloride USP monohydrate, lidocaine solution,4%, lidocaine cream, 4%, lidocaine and prilocaine cream, 2.5%/2.5%, orcombination thereof.

Additionally or alternatively, the topical composition may includebetween 1 mg and about 50 mg per gram of prilocaine or pharmaceuticallyacceptable salt or equivalent thereof from bulk powder. For example, thetopical composition may comprise prilocaine hydrochloride USP powder inan amount between 1 mg and 50 mg per gram such as between about 1 mg andabout 10 mg, about 5 mg and about 15 mg, about 10 mg and about 20 mg,about 15 mg and about 25 mg, about 20 mg and about 30 mg, about 25 mgand about 35 mg, about 30 mg and about 40 mg, about 35 mg and about 45mg, about 40 mg and about 50 mg, about 5 mg and about 25 mg, about 5 mgand about 30 mg, about 5 mg and about 45 mg, or greater than or equal toabout 1 mg, about 3 mg, about 5 mg, about 6 mg, about 8 mg, about 9 mg,about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about16 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, or less than or equal to about 3 mg, about 5 mg, about 10mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, or about 50 mg per gram of topicalcomposition. In an example, the topical composition includes about 1 mg,about 3 mg, about 5 mg, about 6 mg, about 8 mg, about 9 mg, about 10 mg,about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 16 mg, about20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,or about 50 mg of prilocaine hydrochloride USP powder per gram oftopical composition. Other bulk powders of prilocaine salts orpharmaceutical equivalents may be used in addition or alternatively toprilocaine hydrochloride USP in weights providing like amounts ofprilocaine active.

Various embodiments of the topical composition may include aboutequivalent amounts of lidocaine and prilocaine by weight of the topicalcomposition. Some embodiments may include unmatched amounts of lidocaineand prilocaine.

In one embodiment, a method of making the topical composition mayinclude combining the contents of a capsule comprising cannabidiolsynthetic powder and xylitol and/or poloxamer with a solution,suspension, cream, gel, ointment, lotion, or emulsion. The capsule mayinclude between about 5 mg and about 100 mg, such as between about 10 mgand about 50 mg cannabidiol, for example. The solution, suspension,cream, gel, ointment, lotion, or emulsion may comprise a commerciallyavailable base or medicated composition. Ointments may includepetrolatum, mineral oil, paraffins, synthetic hydrocarbons, waterwashable ointments, hydrophilic ointments, water containing ointments orointments devoid of water. Solutions or suspensions may comprise aqueousor non-aqueous solutions. In a further embodiment, the method of makingthe topical composition comprises combining one or more additionalactive agents. The one or more additional active agents may be selectedfrom any active agents, such as those and in amounts described herein.The method may include combining the contents of the capsule with theone or more additional active agents within a solution, cream, gel,ointment, lotion, or emulsion or combining with the same to formulatethe topical composition. Some embodiments may include other additionalcomponents or composition thereof in addition to or instead of thoseidentified above and elsewhere herein. In various embodiments, thetopical composition comprises cannabidiol, an NSAID agent, and a localanesthetic agent. The representative amount of cannabidiol, NSAID, andlocal anesthetic active agents and actives thereof, e.g., diclofenac,lidocaine, and prilocaine, in the topical composition may be asdescribed above and elsewhere herein. For example, the capsule may becombined with diclofenac, lidocaine, and prilocaine to formulate atopical composition comprising between about 1% and about 1.5%diclofenac, between about 1.9% and about 2.5% lidocaine, and betweenabout 1.9% and about 2.5% prilocaine by weight. In an example, thecapsule may be combined with a cream containing about 1.5% diclofenac,2.5% lidocaine, and 2.5% prilocaine by weight. In one example, thetopical composition comprises between about 0.5% and about 20%cannabidiol, such as between about 2% and about 17% cannabidiol byweight.

Various examples of a topical composition comprising between about 0.1%and about 20% cannabidiol, between about 0.1% and about 4% diclofenac,between about 0.1% and about 4% lidocaine, and between about 0.1% andabout 4% prilocaine by weight are described below and elsewhere herein.In such examples, the topical composition may be compounded by combiningcommercially available compositions including the actives such asdiclofenac sodium topical solution, 1.5% (w/w), and lidocaine andprilocaine 2.5%/2.5%. Further examples may also include combininglidocaine hydrochloride topical solution, 4%. Further examples mayadditionally or alternatively include diclofenac sodium USP powder,lidocaine hydrochloride USP monohydrate powder, prilocaine hydrochlorideUSP powder, or combination thereof.

In one example, the topical composition comprises a topical pain creamcomprising between about 0.5% and about 20% cannabidiol, between about0.5% and about 2% diclofenac sodium, between about 1% and about 3%lidocaine, and between about 1% and about 3% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 0.1% and about 17% cannabidiol, betweenabout 0.75% and about 2% diclofenac sodium, between about 1.5% and about3% lidocaine, and between about 1.5% and about 3% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 17% cannabidiol, betweenabout 1% and about 2% diclofenac sodium, between about 2% and about 3%lidocaine, and between about 2% and about 3% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 15% cannabidiol, betweenabout 1.25% and about 2% diclofenac sodium, between about 1.5% and about3% lidocaine, and between about 1.5% and about 3% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 3.3% and about 15% cannabidiol, betweenabout 1% and about 1.75% diclofenac sodium, between about 1.75% andabout 3% lidocaine, and between about 1.75% and about 3% prilocaine byweight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 17% cannabidiol, betweenabout 1.25% and about 1.75% diclofenac sodium, between about 1.75% andabout 3% lidocaine, and between about 1.75% and about 3% prilocaine byweight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 10% cannabidiol, betweenabout 1.25% and about 1.75% diclofenac sodium, between about 2% andabout 3% lidocaine, and between about 2% and about 3% prilocaine byweight.

In another example, the topical composition comprises a topical paincream comprising between about 0.5% and about 5% cannabidiol, betweenabout 1.5% and about 2% diclofenac sodium, between about 2.25% and about3% lidocaine, and between about 2.25% and about 3% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 20% cannabidiol, betweenabout 1.5% and about 2% diclofenac sodium, between about 2.5% and about3% lidocaine, and between about 2.5% and about 3% prilocaine by weight.

In another example, the topical composition comprises a topical paincomprising between about 2% and about 17% cannabidiol and greater thanor equal to each of about 1.15% diclofenac sodium, about 2% lidocaine,and about 2% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 20% cannabidiol and greaterthan or equal to each of about 1.5% diclofenac sodium, about 2.5%lidocaine, and about 1.5% prilocaine by weight.

In another example, the topical composition comprises a topical paincream comprising between about 2% and about 20% cannabidiol and greaterthan about 4% diclofenac sodium, less than about 4% lidocaine, and lessthan about 4% prilocaine by weight.

Some embodiments of the above examples may include about equivalentamounts of lidocaine and prilocaine by weight of the topicalcomposition.

In the above examples, or in other examples or embodiments describedherein, compounding the topical composition may comprise combining about5 mg and about 50 mg cannabidiol, at least diclofenac sodium topicalsolution, 1.5% (w/w), lidocaine and prilocaine cream, 2.5%/2.5%, as wellas combining one or more of diclofenac sodium UPS bulk powder, lidocainehydrochloride topical solution, 4%, lidocaine hydrochloride USPmonohydrate powder, or prilocaine hydrochloride USP powder in amountsdescribed in the following paragraphs and elsewhere herein. In someembodiments, the cannabidiol comprises cannabidiol synthetic analoguepowder. In one embodiment, the cannabidiol is provided in a capsuleincluding xylitol and/or poloxamer as described elsewhere herein.

Diclofenac sodium topical solution, 1.5% (w/w), may be combined in anamount between about 10% and about 75% diclofenac sodium topicalsolution, 1.5% (w/w), by weight of the topical composition, for examplebetween about 10% and about 65%, about 20% and about 50%, about 20% andabout 60%, about 30% and about 60%, about 30% and about 55%, about 30%and about 50%, or about 35% and about 45%, or a non-zero percent lessthan or equal to about 70%, about 60%, about 50%, about 45%, about 40%,about 35%, about 25%, about 15% by weight of the topical composition. Insome embodiments, diclofenac sodium topical solution, 1.5% (w/w), may becompounded in an amount about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, or about 70% by weight of the topical composition.

Lidocaine and prilocaine cream, 2.5%/2.5%, may be combined in an amountbetween about 10% and about 90% lidocaine and prilocaine cream,2.5%/2.5%, by weight of the topical composition, for example betweenabout 20% and about 85%, about 20% and about 65%, about 25% and about60%, about 30% and about 60%, about 35% and about 60%, about 40% andabout 50%, about 45% and about 60%, or about 45% and about 55%, about50% and about 90%, about 50% and about 80%, about 50% and about 70%,about 60% and about 90%, about 60% and about 80%, about 70% and about90%, or a non-zero percent less than or equal to about 90%, about 80%,about 70, about 60%, about 50%, about 45%, about 40%, about 35%, about25%, or about 15% by weight of the topical composition. In someembodiments, lidocaine and prilocaine cream, 2.5%/2.5%, may becompounded in an amount about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 53%, about 55%, about60%, about 65%, or about 70% by weight of the topical composition. Someembodiments may include at least 50% lidocaine and prilocaine cream,2.5%/2.5%, which in some embodiments may include greater than 75%lidocaine and prilocaine cream, 2.5%/2.5%, by weight.

Diclofenac sodium topical solution, 1.5% (w/w), and lidocaine andprilocaine cream, 2.5%/2.5%, may be combined in a combined amountgreater than about 50%, about 60%, about 75%, about 80%, about 85%,about 90%, or about 95% by weight of the topical composition. Examplesmay include diclofenac sodium topical solution, 1.5% (w/w), andlidocaine and prilocaine cream, 2.5%/2.5%, combined together in anamount between about 50% and about 95%, about 60% and about 95%, about75% and about 95%, about 80% and about 95%, about 85% and about 90%,about 90% and about 95% or less than about 96%, about 95%, about 93%,about 91%, about 85%, about 80%, about 75%, about 70%, or about 60% byweight of the topical composition. Further examples, may includediclofenac sodium topical solution, 1.5% (w/w), and lidocaine andprilocaine cream, 2.5%/2.5%, combined together in an amount about 95%,about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about80%, about 75%, about 70%, or about 60% by weight of the topicalcomposition.

Lidocaine and prilocaine cream, 2.5%/2.5%, and diclofenac sodium topicalsolution, 1.5% (w/w), may be combined at a weight ratio of between about5:1 and about 1:5, for example between about 4:1 and about 1:4, about3:1 and about 1:3, about 2:1 and about 1:2, about 1.5:1 and about 1:1,about 1.3:1 and about 1:1, about 1:1 and about 1:1.5, about 1:1.3, orabout 1:1 and about 1:1.5. In some embodiments, lidocaine and prilocainecream, 2.5%/2.5%, and diclofenac sodium topical solution, 1.5% (w/w),may be combined at a weight ratio of about 5:1, about 4:1, about 3:1,about 2:1, about 1.5:1, about 1.3:1, about 1:1, about 1:1.3, about1:1.5, about 1:2, about 1:3, about 1:4, or about 1:5.

Lidocaine hydrochloride topical solution, 4%, may be combined in anamount between 0 and about 20%, or between about 1% and about 7%, byweight of the topical composition, for example between about 1% andabout 17%, about 1% and about 15%, about 1% and about 12%, about 1% andabout 10%, about 1% and about 7%, about 1% and about 5%, about 1% andabout 3%, about 2% and about 7%, or a non-zero percent less than orequal to about 20%, about 18%, about 15%, about 13%, about 10%, about7%, about 5%, or about 3% by weight of the topical composition. In someembodiments, lidocaine hydrochloride topical solution, 4%, may becompounded in an amount about 20%, about 18%, about 15%, about 13%,about 10%, about 7%, about 5%, about 3%, about 2%, or about 0.9% byweight of the topical composition.

Lidocaine and prilocaine cream, 2.5%/2.5%, and lidocaine hydrochloridetopical solution, 4%, may be combined in some examples at a weight ratioof between about 800:1 and about 1:4, for example between about 800:1and about 1:2, about 400:1 and about 1:1, about 400:1 and about 10:1,about 200:1 and about 10:1, about 100:1 and about 10:1, about 75:1 andabout 10:1, about 60:1 and about 25:1, about 55:1 and about 35:1, about55:1 and about 40:1, about 55:1 and about 45:1, or about 53:1 and about50:1. In some embodiments, lidocaine and prilocaine cream, 2.5%/2.5%,and lidocaine hydrochloride topical solution, 4%, may be combined at aweight ratio of about 800:1, about 400:1, about 200:1, about 100:1,about 75:1, about 65:1, about 60:1, about 55:1, about 53:1, about 52:1,about 50:1, about 45:1, about 40:1, about 30:1, about 20:1, about 4:1,about 2:1, about 1:1, about 1:2, or about 1:4.

Diclofenac sodium USP powder may be combined in an amount between 0 andabout 10%, or between about 0.5% and about 5%, by weight of the topicalcomposition, for example between about 0.1% and about 5%, about 1% andabout 5%, about 1% and about 3%, about 1% and about 2%, about 2% andabout 5%, about 2% and about 3%, about 0.5% and about 1.5%, or about0.5% and about 1%, or a non-zero percent less than or equal to about 5%,about 4.5%, about 3.5%, about 2.5%, about 2%, about 1.5%, about 1.4%,about 1.1%, about 1.0%, about 0.8%, about 0.6%, about 0.5%, or about0.1% by weight of the topical composition. In some embodiments,diclofenac sodium USP powder may be compounded in an amount about 5%,about 4.5%, about 3.5%, about 2.5%, about 2%, about 1.5%, about 1.4%,about 1.1%, about 1.0%, about 0.8%, about 0.6%, about 0.5%, or about0.1% by weight of the topical composition.

Diclofenac sodium topical solution, 1.5% (w/w), and diclofenac sodiumUSP powder may be combined at a weight ratio of between about 800:1 andabout 1:4, for example between about 400:1 and about 1:2, about 200:1and about 1:1, about 100:1 and about 1:1, about 75:1 and about 10:1,about 60:1 and about 25:1, about 50:1 and about 35:1, about 45:1 andabout 35:1, or about 42:1 and about 38:1. In some embodiments,diclofenac sodium topical solution, 1.5% (w/w), and diclofenac sodiumUSP powder may be combined at a weight ratio of about 800:1, about400:1, about 200:1, about 100:1, about 75:1, about 60:1, about 50:1,about 45:1, about 42:1, about 40:1, about 38:1, about 35:1, about 25:1,about 10:1, about 1:1, or about 4:1.

Lidocaine hydrochloride USP monohydrate powder may be combined in anamount between 0 and about 6%, or between about 0.75% and about 5%, byweight of the topical composition, for example between about 0.5% andabout 5%, about 0.5% and about 4.5%, about 0.5% and about 3.5%, about0.5% and about 2.5%, about 0.5% and about 1.5%, about 1.5% and about 5%,about 1.5% and about 3.5%, about 2% and about 5%, about 3.5% and about5%, or a non-zero percent less than or equal to about 6%, about 5%,about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.75%, about1.5%, about 1.25%, about 1%, or about 0.5% by weight of the topicalcomposition. In some embodiments, lidocaine hydrochloride USPmonohydrate powder may be compounded in an amount about 6%, about 5%,about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.75%, about1.5%, about 1.25%, about 1%, or about 0.5% by weight of the topicalcomposition.

Lidocaine and prilocaine cream, 2.5%/2.5%, and lidocaine hydrochlorideUSP monohydrate powder may be combined in some examples at a weightratio of between about 800:1 and about 1:4, for example between about800:1 and about 1:2, about 400:1 and about 1:1, about 400:1 and about10:1, about 200:1 and about 10:1, about 100:1 and about 10:1, about 75:1and about 10:1, about 60:1 and about 25:1, about 55:1 and about 30:1,about 50:1 and about 30:1, about 45:1 and about 35:1, or about 40:1 andabout 35:1. In some embodiments, lidocaine and prilocaine cream,2.5%/2.5%, and lidocaine hydrochloride USP monohydrate powder may becombined at a weight ratio of about 800:1, about 400:1, about 200:1,about 100:1, about 75:1, about 65:1, about 60:1, about 55:1, about 50:1,about 45:1, about 40:1, about 38:1, about 35:1, about 30:1, about 20:1,about 4:1, about 2:1, about 1:1, about 1:2, or about 1:4.

Prilocaine hydrochloride USP powder may be combined in an amount between0 and about 6%, or between about 0.75% and about 5%, by weight of thetopical composition, for example between about 0.5% and about 5%, about0.5% and about 4.5%, about 0.5% and about 3.5%, about 0.5% and about2.5%, about 0.5% and about 1.5%, about 1.5% and about 5%, about 1.5% andabout 3.5%, about 2% and about 5%, about 3.5% and about 5%, or anon-zero percent less than or equal to about 6%, about 5%, about 4%,about 3.5%, about 3%, about 2.5%, about 2%, about 1.75%, about 1.5%,about 1.25%, about 1%, or about 0.5% by weight of the topicalcomposition. In some embodiments, prilocaine hydrochloride USP powdermay be compounded in an amount about 6%, about 5%, about 4%, about 3.5%,about 3%, about 2.5%, about 2%, about 1.75%, about 1.5%, about 1.25%,about 1%, or about 0.5% by weight of the topical composition.

Lidocaine and prilocaine cream, 2.5%/2.5%, and prilocaine hydrochlorideUSP powder may be combined in some examples at a weight ratio of betweenabout 800:1 and about 1:4, for example between about 800:1 and about1:2, about 400:1 and about 1:1, about 400:1 and about 10:1, about 200:1and about 10:1, about 100:1 and about 10:1, about 75:1 and about 10:1,about 60:1 and about 25:1, about 55:1 and about 30:1, about 50:1 andabout 30:1, about 45:1 and about 35:1, or about 40:1 and about 35:1. Insome embodiments, lidocaine and prilocaine cream, 2.5%/2.5%, andprilocaine hydrochloride USP powder may be combined at a weight ratio ofabout 800:1, about 400:1, about 200:1, about 100:1, about 75:1, about65:1, about 60:1, about 55:1, about 50:1, about 45:1, about 40:1, about38:1, about 35:1, about 30:1, about 20:1, about 4:1, about 2:1, about1:1, about 1:2, or about 1:4.

The example topical compositions may also include one or more additionalcomponents such as one or more of stabilizers or preservatives,thickeners, surfactants, emulsifiers, solubilizes, skin or penetrantenhancers, emollients, or gelling agents. Stabilizers or preservativesmay include, for example, one or more of disodium EDTA or a paraben(e.g., methylparaben, propylparaben). In one embodiment, the compoundedcomposition includes one or both of methylparaben or propylparaben.Thickening, which may include gelling, agents may be added to increaseviscosity, consistency, or thicken the composition to formulate alotion, cream, or gel and may include, for example, one or more ofacrylic acid or an acrylate, carbomer, carboxypolymethylene,hydroxyethyl cellulose, microcrystalline cellulose,carboxymethylcellulose, polyethylene glycol, waxes, or titanium dioxide.In various embodiments, the topical composition comprises between about0.5% and about 7% thickening agent by weight, such as between about 1%and about 5%. Surfactants or emulsifiers may also be added to emulsifyor improve consistency and may include, for example, one or more of anacrylic, carbomer, polysorbate (e.g., polysorbate 85, polysorbate 20),or emulsifying wax. Solubilizers may include, for example, alcohols ordimethyl isosorbide. Skin or penetrant enhancers may include, forexample, one or more of DMSO or isopropyl myristate. In someembodiments, the topical composition may comprise xylitol, poloxamers,or both. In one example, the topical composition may include a blend ofmicronized xylitol and poloxamers sold under the mark LOXASPERSE®. Inone such example, LOXASPERSE® is present in an amount between about0.05% and about 2% by weight. Some embodiments may include otheradditional components or composition thereof in addition to or insteadof those identified above and elsewhere herein. In some embodiments,LOXASPERSE®

In some embodiments, the example topical composition comprises between0.5% and 20% by weight of one or more additional actives, such asanticonvulsants, nerve depressants, muscle relaxants, NMDA(N-Methyl-D-aspartate) receptor antagonists, opiate or opioid agonists,antidepressants, and/or other active agents.

In one embodiment, the topical composition may comprise between about0.25% and about 20% cannabidiol, about 1.25% diclofenac sodium, about2.25% lidocaine, and about 2.25% prilocaine by weight.

In one such example, the topical composition comprises a topical paincream having between about 5 mg and about 100 mg or between about 10 mgand about 50 mg cannabidiol, about 0.4 g diclofenac sodium 1.5%solution, about 0.009 g diclofenac sodium USP powder, about 0.528 glidocaine and prilocaine cream, 2.5%/2.5%, about 0.014 g lidocainehydrochloride USP monohydrate, about 0.01 g lidocaine hydrochloride 4%solution, and about 0.0138 g prilocaine hydrochloride USP per gram ofthe topical composition. Each gram of the topical composition mayinclude about 15 mg diclofenac sodium and about 25 mg of each oflidocaine and prilocaine. The topical composition comprises about 40% byweight diclofenac sodium 1.5% solution providing about 6 mg diclofenacsodium, about 0.9% by weight diclofenac sodium USP powder providingabout 9 mg diclofenac sodium, about 52.8% by weight lidocaine andprilocaine cream, 2.5%/2.5%, providing about 13.2 mg of each oflidocaine and prilocaine, about 1.4% by weight lidocaine hydrochlorideUSP monohydrate providing about 11.4 mg of lidocaine, about 1% by weightlidocaine hydrochloride, 4%, solution providing about 0.4 mg oflidocaine, and about 1.38% by weight prilocaine hydrochloride USPproviding about 13.2 mg of prilocaine. In an another embodiment, thecompounded composition does not include lidocaine hydrochloride topicalsolution, 4%, and includes about 0.0145 g or about 1.45% by weightlidocaine hydrochloride USP monohydrate providing about 11.8 mglidocaine. In one formulation, a topical base cream is used instead ofor in addition to lidocaine and prilocaine cream, 2.5%/2.5%.

In one embodiment, the topical composition may comprise between about0.5% and about 20% cannabidiol, about 1.5% diclofenac sodium, about 3%lidocaine, and about 3% prilocaine by weight.

In one such example, the topical composition comprises a topical paincream having about 0.3 g diclofenac sodium 1.5% solution, about 0.0105 gdiclofenac sodium USP powder, about 0.65 g lidocaine and prilocainecream, 2.5%/2.5%, about 0.012 g lidocaine hydrochloride USP monohydrate,about 0.1 g lidocaine hydrochloride, 4%, solution, and about 0.016 gprilocaine hydrochloride USP per gram of the topical composition. Eachgram of the topical composition may include about 15 mg diclofenacsodium and about 30 mg of each of lidocaine and prilocaine. The topicalcomposition comprises about 30% by weight diclofenac sodium 1.5%solution providing about 4.5 mg diclofenac sodium, about 1.05% by weightdiclofenac sodium USP powder providing about 10.5 mg diclofenac sodium,about 65% by weight lidocaine and prilocaine cream, 2.5%/2.5%, providingabout 16.75 mg of each of lidocaine and prilocaine, about 1.2% by weightlidocaine hydrochloride USP monohydrate providing about 12 mg oflidocaine, about 10% by weight lidocaine hydrochloride, 4%, solutionproviding about 4 mg of lidocaine, and about 1.6% by weight prilocainehydrochloride USP providing about 13.75 mg of prilocaine. In an anotherembodiment, the compounded composition does not include lidocainehydrochloride topical solution, 4%, and includes about 0.017 g or about1.7% by weight lidocaine hydrochloride USP monohydrate providing about13.75 mg lidocaine. In one formulation, a topical base cream is usedinstead of or in addition to lidocaine and prilocaine cream, 2.5%/2.5%.

The above example embodiments of the topical composition may alsoinclude a thickening agent, a preservative, or both. For example, thethickening agent may comprise between about 1% and about 5% by weight ofthe topical composition. For example, between about 1% and about 5% byweight hydroxyethyl cellulose. In one embodiment, the thickening agentmay comprise hydroxyethyl cellulose is an amount about 0.02 g per gramof topical composition. The preservative may include paraben. Forexample, the preservative may comprise methylparaben, propylparaben, orboth. In one formulation methylparaben is combined in an amount betweenabout 0.1 mg and about 1 mg, e.g., about 0.25 mg, and propylparaben iscombined in an amount between 0.1 mg and about 1 mg, e.g., about 0.125mg, per gram of the topical composition. Xylitol, poloxamers, or bothmay also be included. For example, the topical composition may includebetween 1 mg and 20 mg of xylitol, poloxamers, or both. In oneembodiment, the topical composition contains up to 5% LOXASPERSE®, suchas about 5 mg LOXASPERSE®. In at least one embodiment, the topicalcomposition includes greater than 5% LOXASPERSE® by weight.

Combining the ingredients may include mixing the ingredients to generatea smooth consistent cream. In one example, the ingredients may be addedto a mixing bowl and then mixed to thoroughly wet powders with the creamand/or solutions. The mixed ingredients may be further milled, forexample, with a three-roll mill and then packaged.

Some embodiments may not include a commercially available lidocainesolution such as a lidocaine hydrochloride topical solution, 4%. Onesuch embodiment or another embodiment may not include one or more of alidocaine, prilocaine, or diclofenac bulk powder. A method of making anabove or another embodiment of the topical composition described herein,may not include combining additional thickening agents, preservatives,or both, not already present in the combined commercially availablemedicated compositions, e.g., diclofenac sodium topical solution, 1.5%(w/w), lidocaine hydrochloride topical solution, 4%, or lidocaine andprilocaine cream, 2.5%/2.5%.

In various embodiments, the topical pain cream may also include one ormore active drugs selected from an local anesthetics, NSAIDS,analgesics, antidepressants, anticonvulsants, opioids, NMDA receptorantagonists, muscle relaxants, or combination thereof.

For example, the topical composition may include a topical pain creamincluding cannabidiol, lidocaine hydrochloride topical solution, 4% andone or more additional actives comprising an NSAID wherein the NSAID isselected from one or more salicylic acid derivatives (e.g., aspirin,diflunisal, salsalate, trilisate), one or more propionic acids (e.g.,flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin), one or moreacetic acids (e.g., diclofenac, etodolac, indomethacin, ketorolac,nabumetone, sulindac, tolmetin), one or more fenamates (e.g.,meclofenamate), one or more oxicams (meloxicam, piroxicam), or one ormore COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib), orcombinations thereof. For example, in one embodiment, the topicalcomposition comprises a topical pain cream including xylitol, poloxamer,and one or more actives comprising an comprising a benzeneacetic acidderivative such as diclofenac. Various embodiments may include betweenabout 0.01% and about 20% by weight NSAID.

In an above or another example, the topical composition may include atopical pain cream including cannabidiol, lidocaine hydrochloridetopical solution, 4% and one or more actives comprising a localanesthetic selected from lidocaine, prilocaine, benzocaine, orcombination thereof. Various embodiments may include between about 0.01%and about 10% by weight local anesthetic.

In an above or another example, the topical composition may include atopical pain cream including cannabidiol, lidocaine hydrochloridetopical solution, 4% and one or more actives comprising ananticonvulsant, which may include nerve depressant, selected fromgabapentin, topiramate, lamotrigine, or combinations thereof. In variousembodiments, the anticonvulsant or nerve depressant agent may comprisebetween about 0.01% and about 20% by weight of the topical pain cream.

In an above or another example, the topical composition may include atopical pain cream including cannabidiol, lidocaine hydrochloridetopical solution, 4% and one or more actives comprising a NMDA receptorantagonists such as ketamine.

In an above or another example, the topical composition may include atopical pain cream including cannabidiol, lidocaine hydrochloridetopical solution, 4% and one or more actives comprising an opiate, whichmay include an opioid agonist, selected from tramadol; one or more C2opiate agonists selected from oxycodone, morphine, methadone,hydromorphone, and fentanyl; one or more C3 opiate agonists selectedfrom hydrocodone, codeine, propoxyphene, butalbital, and pentazocine; orany combination thereof.

In an above or another example, the topical composition may include atopical pain cream including cannabidiol, lidocaine hydrochloridetopical solution, 4% and one or more actives comprising a musclerelaxant comprising one or more muscle relaxants selected from baclofen,carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam,metaxalone, methocarbamol, orphenadrine, quinine sulfate, tizanidine,and/or other muscle relaxants. In various embodiments, the musclerelaxant agent comprises between about 0.001% and about 5% by weight ofthe topical pain cream.

In an above or another example, the topical composition may include atopical pain cream including cannabidiol, lidocaine hydrochloridetopical solution, 4% and one or more actives including a NSAID includingdiclofenac and a local anesthetic including lidocaine and prilocaine. Inone embodiment, lidocaine may be provided by a lidocaine solution,lidocaine and prilocaine cream, lidocaine bulk powder, or both.Diclofenac may be provided by a diclofenac solution, diclofenac bulkpowder, or both, for example. In a further embodiment, the compositionmay include xylitol, one or more poloxamers, or both.

In various embodiments, a method of compounding a topical pain creamcomprises formulating a cream comprises combining cannabidiol at aweight percent between about 0.1% and about 20% and lidocainehydrochloride topical solution, 4% in a weight percent between about0.1% and about 7% or in another weight percent described above orelsewhere herein. The method may also include combining one or moreactive drugs introduced above selected from an analgesics, localanesthetics, NSAIDS, antidepressants, anticonvulsants, opioids, NMDAreceptor antagonists, muscle relaxants, or combination thereof.

In one example, the method includes combining the ingredients with acream base or another base that when mixed with the ingredients, whichmay include additional ingredients such as thickeners, water, alcohol,solvents, emulsifiers, emollients, for example, generates a cream. Forexample, ingredients including water or alcohol may be combined with ananhydrous base. In some embodiments, the base includes a commerciallyavailable base, such as a cream base, for compounding. In oneembodiment, all or a portion of the base portion, such as a cream base,is provided by a commercially available medicated topical cream,ointment, paste, or solution. In one example, the method includescombining the ingredients with components of a cream base, such asthickeners, surfactants, emulsifiers, water, alcohol, solvents, oils,waxes, hydrocarbons, emollients, or combination thereof. Thickening orgelling agents may include, for example, one or more of acrylic acid oran acrylate, carbomer, carboxypolymethylene, cellulose, hydroxyethylcellulose, microcrystalline cellulose, carboxymethylcellulose,polyethylene glycol, stearyl palmitate, cetyl alcohol, waxes, titaniumdioxide, or combination thereof. Some embodiments may include otherthickening or gelling agents may be used in addition to or instead ofthose identified above and elsewhere herein. Surfactants or emulsifiersmay include, for example, one or more of an acrylic, carbomer,polysorbate (e.g., polysorbate 85, polysorbate 20), sorbitan stearate,glyceryl stearate, stearic acid, or emulsifying wax. Some embodimentsmay include other surfactants or emulsifiers in addition to or insteadof those identified above and elsewhere herein. Solvents may include,for example, alcohols or dimethyl isosorbide.

Some embodiments may include addition of one or more of stabilizers orpreservatives, solubilizes, skin or penetrant enhancers, emollients, orcombination thereof. Some embodiments may include other solvents inaddition to or instead of those identified above and elsewhere herein.Stabilizers or preservatives may include, for example, one or more ofdisodium EDTA or a paraben (e.g., methylparaben, propylparaben). Someembodiments may include other stabilizers in addition to or instead ofthose identified above and elsewhere herein. Skin penetrant enhancersmay include, for example, one or more of DMSO or isopropyl myristate.Some embodiments may include other skin penetrant enhancers in additionto or instead of those identified above and elsewhere herein. Emollientsmay include, for example, natural oils, mineral oil, castor oil,hydrocarbons, antioxidants, lanolin alcohol, or combination thereof.Some embodiments may include other emollients in addition to or insteadof those identified above and elsewhere herein.

In various embodiments, the topical composition may include a topicalpain cream, solution, suspension, gel, emulsion, or ointment comprisingcannabidiol, xylitol and one or more poloxamers and/or one or moreactive drugs selected from an local anesthetics, NSAIDS, analgesics,antidepressants, anticonvulsants, opioids, NMDA receptor antagonists,muscle relaxants, or combination thereof.

In various embodiments, the topical composition comprises a topical paincream including cannabidiol and a combination of xylitol and one or morepoloxamers. The combination of xylitol and one or more poloxamers may bepresent in a non-zero amount to about 10% by weight, such as betweenabout 0.5% and about 10%, about 0.5% and about 7%, about 0.5% and about5%, about 0.5% and about 2%, about 1% and about 10%, about 0.5% andabout 7%, about 1% and about 5%, about 1% and about 3%, about 2% andabout 7%, about 2% and about 5%, about 3% and about 7%, or about 3% andabout 5% by weight of the topical pain cream. In one embodiment, the oneor more poloxamers comprise poloxamer 407 and poloxamer 188.

For example, the topical composition comprises a topical pain creamsolution, suspension, gel, emulsion, or ointment including cannabidiol,xylitol, and one or more poloxamers and/or one or more activescomprising an NSAID wherein the NSAID is selected from one or moresalicylic acid derivatives (e.g., aspirin, diflunisal, salsalate,trilisate), one or more propionic acids (e.g., flurbiprofen, ibuprofen,ketoprofen, naproxen, oxaprozin), one or more acetic acids (e.g.,diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac,tolmetin), one or more fenamates (e.g., meclofenamate), one or moreoxicams (meloxicam, piroxicam), or one or more COX-2 inhibitors (e.g.,celecoxib, rofecoxib, valdecoxib), or combinations thereof. For example,in one embodiment, the topical composition comprises a topical paincream solution, suspension, gel, emulsion, or ointment includingcannabidiol, xylitol, poloxamer, and one or more actives comprising ancomprising a benzeneacetic acid derivative such as diclofenac. Variousembodiments may include between about 0.01% and about 20% by weightNSAID.

In an above or another example, the topical composition comprises atopical pain cream including cannabidiol, xylitol and/or one or morepoloxamers and one or more actives comprising a local anestheticselected from lidocaine, prilocaine, benzocaine, or combination thereof.Various embodiments may include between about 0.01% and about 10% byweight local anesthetic.

In an above or another example, the topical composition comprises atopical pain cream solution, suspension, gel, emulsion, or ointmentincluding cannabidiol, xylitol, poloxamer, and one or more activescomprising an anticonvulsant, which may include nerve depressant,selected from gabapentin, topiramate, lamotrigine, or combinationsthereof. In various embodiments, the anticonvulsant or nerve depressantagent may comprise between about 0.01% and about 20% by weight of thetopical pain cream.

In an above or another example, the topical composition comprises atopical pain cream solution, suspension, gel, emulsion, or ointmentincluding cannabidiol, xylitol, poloxamer, and one or more activescomprising a NMDA receptor antagonists such as ketamine.

In an above or another example, the topical composition comprises atopical pain cream solution, suspension, gel, emulsion, or ointmentincluding cannabidiol, xylitol, poloxamer, and one or more activescomprising an opiate, which may include an opioid agonist, selected fromtramadol; one or more C2 opiate agonists selected from oxycodone,morphine, methadone, hydromorphone, and fentanyl; one or more C3 opiateagonists selected from hydrocodone, codeine, propoxyphene, butalbital,and pentazocine; or any combination thereof.

In an above or another example, the topical composition comprises atopical pain cream solution, suspension, gel, emulsion, or ointmentincluding cannabidiol, xylitol, poloxamer, and one or more activescomprising a muscle relaxant comprising one or more muscle relaxantsselected from baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine,dantrolene, diazepam, metaxalone, methocarbamol, orphenadrine, quininesulfate, tizanidine, and/or other muscle relaxants. In variousembodiments, the muscle relaxant agent comprises between about 0.001%and about 5% by weight of the topical pain cream.

In an above or another example, the topical composition comprises atopical pain cream solution, suspension, gel, emulsion, or ointmentincluding cannabidiol, xylitol, poloxamer, and one or more activesincluding a NSAID including diclofenac and a local anesthetic includinglidocaine and prilocaine. In one embodiment, lidocaine may be providedby a lidocaine solution, lidocaine and prilocaine cream, lidocaine bulkpowder, or both. Diclofenac may be provided by a diclofenac solution,diclofenac bulk powder, or both, for example. In one example,cannabidiol is present in an amount between about 0.25% and about 5%,diclofenac is present in an amount between about 1% and about 2%, andlidocaine and prilocaine are each present in an amount between about 2%and about 3% by weight.

In various embodiments, a method of compounding a topical pain creamcomprises formulating a cream comprising combining cannabidiol, xylitol,and one or more poloxamers in a weight percent between about 0.1% andabout 25% or in another weight percent described above or elsewhereherein. In one embodiment, the one or more poloxamers comprise poloxamer407 and poloxamer 188. The method may also include combining one or moreactive drugs selected from an analgesics, local anesthetics, NSAIDS,antidepressants, anticonvulsants, opioids, NMDA receptor antagonists,muscle relaxants, or combination thereof.

The topical compositions comprising a topical pain suspension, cream,gel, lotion, ointment, or emulsion described herein may comprise a watercontent of about 5% or more. For example, the water content may bebetween about 5% and about 80%, about 5% and about 70%, about 5% andabout 65%, about 5% and about 50%, about 5% and about 25%, about 5% andabout 15%, about 10% and about 80%, about 10% and about 60%, about 10%and about 45%, about 10% and about 25%, about 10% and about 15%, about20% and about 80%, about 20% and about 60%, about 20% and about 45%,about 20% and about 25%, about 30% and about 80%, about 30% and about60%, about 30% and about 45%, about 40% and about 80%, about 40% andabout 60%, about 40% and about 50%, about 50% and about 80%, about 50%and about 70%, about 50% and about 60%, about 60% and about 80%, about60% and about 70%, about 70% and about 80%, about 8% or greater, about10% or greater, about 15% or greater, about 20% or greater, about 25% orgreater, about 30% or greater, about 35% or greater, about 45% orgreater, about 55% or greater, about 65% or greater, about 75% orgreater, about 80%. In one embodiment, the water content may be about80% or greater. In another embodiment, the water content may be lessthan 5%.

The topical composition may be topically applied for treatment of anailment, e.g., by topically contacting the composition to skin ormucosal surfaces such as by spreading or layering there along. In oneexample, an occlusive dressing may be applied. The topical compositionor derivative thereof may be topically applied to a body surfaceutilizing for example, spray, drops, atomizer, wash, swab, sponge,absorbent dressing, instillation or irrigation. An occlusive materialmay also be used in some embodiments, Topical application may be withrespect to body surfaces such as trunk, limbs, hands, feet, neck, head,cavities, etc. In various embodiments, the topical composition may findorthopedic application, e.g., as part of a therapeutic treatment ofrheumatoid arthritis/osteoarthritis, lateral epicondylitis (tenniselbow), medial epicondylitis (golfer's elbow), chondromalaciapatellae—CMP (runner's knee), or tendonitis/carpel tunnel; rheumatologicapplication, e.g., as part of a therapeutic treatment of soft tissuepain, fibromyalgia, diabetic neuropathy, peripheral neuropathy,rheumatoid arthritis, or osteoarthritis; neurologic application, e.g.,as part of a therapeutic treatment diabetic neuropathy, peripheralneuropathy, fibromyalgia, or localized pain; podiatric application,e.g., as part of a therapeutic treatment of diabetic neuropathy,peripheral neuropathy, plantar fasciitis, Achilles tendonitis, tarsaltunnel—post-op massage, or heel pain—which may include usage inconjunction with urea; pain management application, e.g., as part of atherapeutic treatment of soft tissue pain, fibromyalgia,diabetic/peripheral neuropathy, rheumatoid arthritis, osteoarthritis, orneck and back pain; or ear nose and throat or dental applications, e.g.,as part of a therapeutic treatment of temporomandibular joint disorder(TMJD or TMJ), or trigeminal neuralgia.

The present disclosure may be embodied in other forms without departingfrom the spirit or essential attributes thereof and, accordingly,reference should be had to the following claims rather than theforegoing specification as indicating the scope of the invention.Further, the illustrations of arrangements described herein are intendedto provide a general understanding of the various embodiments, and theyare not intended to serve as a complete description. Many otherarrangements will be apparent to those of skill in the art uponreviewing the above description. Other arrangements may be utilized andderived therefrom, such that logical substitutions and changes may bemade without departing from the scope of this disclosure.

This disclosure is intended to cover any and all adaptations orvariations of various embodiments and arrangements of the invention.Combinations of the above arrangements, and other arrangements notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description. Therefore, it is intended thatthe disclosure not be limited to the particular preferred arrangementsdisclosed for carrying out this invention, but that the invention willinclude all embodiments and arrangements falling within the scope of theappended claims.

Various elements described herein have been described as alternatives oralternative combinations, e.g., in a lists of selectable actives,ingredients, or compositions. It is to be appreciated that embodimentsmay include one, more, or all of any such elements. Thus, thisdescription includes embodiments of all such elements independently andembodiments including such elements in all combinations.

The grammatical articles “one”, “a”, “an”, and “the”, as used in thisspecification, are intended to include “at least one” or “one or more”,unless otherwise indicated. Thus, the articles are used in thisspecification to refer to one or more than one (i.e., to “at least one”)of the grammatical objects of the article. By way of example, “acomponent” means one or more components, and thus, possibly, more thanone component is contemplated and may be employed or used in anapplication of the described embodiments. Further, the use of a singularnoun includes the plural, and the use of a plural noun includes thesingular, unless the context of the usage requires otherwise.Additionally, the grammatical conjunctions “and” and “or” are usedherein according to accepted usage. By way of example, “x and y” refersto “x” and “y”. On the other hand, “x or y” refers to “x”, “y”, or both“x” and “y”, whereas “either x or y” refers to exclusivity.

Any numerical range recited herein includes all values and ranges fromthe lower value to the upper value. For example, if a range is stated as1 to 50, it is intended that values such as 2 to 40, 10 to 30, 1 to 3,or 2, 25, 39 and the like, are expressly enumerated in thisspecification. These are only examples of what is specifically intended,and all possible combinations of numerical values and ranges between andincluding the lowest value and the highest value enumerated are to beconsidered to be expressly stated in this application. Numbers modifiedby the term “approximately” or “about” are intended to include +/−10% ofthe number modified.

What is claimed is:
 1. A method of formulating a topical composition foradministration to a skin surface, the method comprising: formulating atopical cream comprising combining: synthetic cannabidiol powder;diclofenac sodium; lidocaine; and prilocaine, wherein the topical creamcomprises between about 1% and about 2% diclofenac sodium, between about2% and about 3% lidocaine, and between about 2.0% and about 3%prilocaine.
 2. The method of claim 1, wherein combining the cannabidiolpowder to formulate the topical cream comprises combining between about10 mg and about 50 mg of the cannabidiol powder into the formulation. 3.The method of claim 2, wherein combining the cannabidiol powdercomprises releasing the cannabidiol powder from a compounded capsule. 4.The method of claim 2, wherein at least a portion of the cannabidiolpowder comprises cannabidiol synthetic powder.
 5. The method of claim 4,wherein the topical cream further comprises between 5% and 20% DMSO. 6.A method of topically treating pain in a subject, the method comprising:topically administering to a skin surface of the subject a topicalcomposition having a solution, cream, gel, suspension, or ointmentformat, wherein the topical composition includes xylitol and betweenabout 10 mg and about 50 mg cannabidiol.
 7. The method of claim 6,wherein the topical composition further includes an NSAID, a localanesthetic, or combination thereof.
 8. The method of claim 7, whereinthe NSAID comprises diclofenac and the local anesthetic compriseslidocaine, prilocaine, or both.
 9. The method of claim 6, whereintopical solution, cream, gel, suspension, or ointment further includesdiclofenac, lidocaine, and prilocaine.
 10. The method of claim 9,wherein the diclofenac is present in an amount between about 0.5% andabout 2% by weight of the topical composition, the lidocaine is presentin an amount between about 1.9% and about 3% by weight of the topicalcomposition, and the prilocaine is present in an amount between about1.9% and about 3% by weight of the topical composition.
 11. The methodof claim 8, wherein topical solution, cream, gel, suspension, orointment further includes between 5% and 20% DMSO.